Extracellular uridine-5′-diphosphate 1 and uridine-5′-diphosphoglucose 2 (FIG. 1) activate the P2Y14 receptor (P2Y14R), a G protein-coupled receptor (GPCR) of the δ-branch of Family A, to modulate function in models of inflammation, diabetes, asthma and other diseases (Lazarowski et al., Mol. Pharmacol. 2015, 88(1), 151-160; and Abbracchio et al., Pharmacol. Rev. 2006, 58, 281-341). This receptor subtype is a member of the P2Y12R-like subfamily of nucleotide receptors, which inhibits the production of cyclic AMP through Gi protein. The P2Y14R promotes hypersensitivity in microglial cells (Kobayashi et al., Glia 2012, 60, 1529-1539), the mobility of neutrophils (Sesma et al., Am. J. Physiol.—Cell Physiol. 2012, 303, C490-C498), the release of mediators from mast cells (Gao et al., Biochem. Pharmacol. 2010, 79, 873-879), inflammation in renal intercalated cells (Azroyan et al., PLoS ONE 2015, 10(3), e0121419. doi:10.1371/joumal.pone.0121419) and mixed effects in insulin function (Xu et al., J. Immunol. 2012, 189(4), 1992-1999; and Meister et al., J. Biol. Chem. 2014, 289, 23353-23366). Thus, approaches to novel antagonists of nucleotide signaling at the P2Y14R would be desirable for exploration as novel therapeutics for treating diseases associated with modulating P2Y14R.
Only a limited set of P2Y14R antagonists are currently known. Several chemotypes based on naphthoic acid and pyrido[4,3-d]pyrimidine have been reported to provide potent P2Y14R antagonists, but displayed low oral bioavailability (International Patent Application WO 2009/070873; Gauthier et al., Bioorg. Med. Chem. Lett. 2011, 21, 2836-2839; Guay et al., Bioorg. Med. Chem. Lett. 2011, 21, 2832-2835; and Robichaud et al., Bioorg. Med. Chem. Lett. 2011, 21, 4366-4368).
Despite these efforts, there remains an unmet need for novel antagonists with improved potency, selectivity, and/or bioavailability for the treatment of disorders that respond to modulating P2Y14R.